Natural killer cells are part of the innate immune system, the primary defense against virus infections and tumors. They may also have a role in activating autoimmune diseases. They lyse their target through forming an activating immunological synapse or they are inhibited by forming an inhibitory synapse with these cells. The goal of this project is to understand how the immunological synapses are formed and how they function. This knowledge may help us to enhance (in the case of virus infection or tumors) or diminish (in the case of autoimmune diseases) their cytolytic activity in circumstances in which this may be desired. The Specific Aim of this proposal is to examine the formation and function of immunological synapses in human Natural Killer (NK) cells by: 1. Identifying the protein components of the actin ring in the peripheral supermolecular activation cluster of the activating NK synapse and the mechanism by which this multiprotein complex is formed, particularly the role of Wiscott-Aldrich Syndrome interacting protein (WIP) and its phosphorylation sites. 2. Studying the signaling pathways that lead to formation of the activating immunological synapse, particularly the phosphorylation of synaptic components and their functions. 3. Defining the role of Myosin IIA and IIB in granule exocytosis, the last step that leads to cytolysis of target cells.